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Compositions and methods for treating heart failure

a technology for heart failure and compositions, applied in the field of compositions and methods for treating heart failure, can solve the problems of cardiovascular event patient death risk of patients, etc., and achieve the effects of improving cardiac function, preventing or reducing the severity of cardiac hypertrophy, and increasing the survival time of heart failure patients

Inactive Publication Date: 2020-03-19
ACCELERON PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent relates to methods of reducing the risk of cardiovascular events and hypertension in patients by administering a BMP antagonist. The BMP antagonist can be administered to patients with heart failure or risk factors for heart failure, such as hypertension, to prevent or treat these conditions. The BMP antagonist can also be used in combination with other active agents or supportive therapies for heart failure. The technical effects of the patent include reducing the risk of cardiovascular events and hypertension in patients and improving cardiac function.

Problems solved by technology

In some embodiments, the risk of death of a patient is from any cause (all-cause mortality).
In some embodiments, the risk of death of a patient is from a cardiovascular event (complication).

Method used

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  • Compositions and methods for treating heart failure
  • Compositions and methods for treating heart failure
  • Compositions and methods for treating heart failure

Examples

Experimental program
Comparison scheme
Effect test

example 1

c Fusion Proteins

[0342]ActRIIA fusion proteins having the extracellular domain of human ActRIIA fused to a human or mouse Fc domain with a linker in between were generated. The constructs are referred to as ActRIIA-hFc and ActRIIA-mFc, respectively.

[0343]ActRIIA-hFc is shown below as purified from CHO cell lines (SEQ ID NO: 50):

ILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCWLDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQPTSNPVTPKPPTGGGTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI

[0344]The ActRIIA-hFc and ActRIIA-mFc proteins were expressed in CHO cell lines. Three different leader sequences were considered:

(i) Honey bee mellitin (HBML):(SEQ ID NO: 51)MKFLVNVALVFMVVYISYIYA(ii) Tissue plasminogen activator (TPA):(SEQ ID NO: 52)MDAMKRGLCCVLLLCGAVFVSP(iii) Native:(SEQ ID NO: 53)MGAAAKLAFAVFLISCSSGA.

[0345]The selected form employs the TPA leader and has the following unprocessed amino acid sequence:

(SEQ ID NO: 54)MDAMKRGLCCVLLLCGAVFVSPGAAILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIV...

example 2

n of ActRIIB-Fc Fusion Proteins

[0350]ActRIIB fusion proteins having the extracellular domain of human ActRIIB fused to a human or mouse Fc domain with a linker in between were constructed. The constructs are referred to as ActRIIB-hFc and ActRIIB-mFc, respectively.

[0351]ActRIIB-hFc is shown below as purified from CHO cell lines (SEQ ID NO: 58):

GRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTGGGTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS

[0352]The ActRIIB-hFc and ActRIIB-mFc proteins were expressed in CHO cell lines. Three different leader sequences were considered: (i) Honey bee mellitin (HBML), ii) Tissue plasminogen activator (TPA), and (iii) Native: MGAAAKLAFAVFLISCSSGA (SEQ ID NO: 59).

[0353]The selected form employs the TPA leader and has the following unprocessed amino acid sequence (SEQ ID NO: 60):

MDAMKRGLCCVLLLCGAVFVSPGASGRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGG...

example 3

n of a BMPRII-Fc Fusion Protein

[0372]A homodimeric BMPRII-Fc fusion protein comprising the extracellular domain of human BMPRII fused to a human immunoglobulin G1 Fc domain with a linker was generated. Leader sequences for use with BMPRII-Fc fusion polypeptide include the native human BMPRII precursor leader, MTSSLQRPWRVPWLPWTILLVSTAAA (SEQ ID NO: 68), and the tissue plasminogen activator (TPA) leader.

[0373]The human BMPRII-Fc polypeptide sequence (SEQ ID NO: 69) with a TPA leader is shown below:

(SEQ ID NO: 69)1MDAMKRGLCC VLLLCGAVFV SPGASQNQER LCAFKDPYQQ DLGIGESRIS51HENGTILCSK GSTCYGLWEK SKGDINLVKQ GCWSHIGDPQ ECHYEECVVT101TTPPSIQNGT YRFCCCSTDL CNVNFTENFP PPDTTPLSPP HSFNRDETGG151GTHTCPPCPA PELLGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP201EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC251KVSNKALPAP IEKTISKAKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG301FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN351VFSCSVMHEA LHNHYTQKSL SLSPGK

[0374]The leader sequence and linker are underlined. T...

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Abstract

In certain aspects, the present disclosure relates to methods of treating, preventing, and reducing the severity or progression of heart failure or one or more complications of heart failure. For example, the disclosure provides various BMP antagonists, such as ActRIIA polypeptides, ActRIIB polypeptides, BMPRII polypeptides, ALKI polypeptides, endoglin polypeptides, BMP 10 propeptide proteins and Fc fusion proteins thereof as well as anti-BMP9 antibodies, for treating, preventing and reducing the severity or progression of heart failure or one or more complications of heart failure.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority from U.S. Provisional Application No. 62 / 455,266, filed Feb. 6, 2017. The specification of the foregoing application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]It has been estimated that over five million people suffer from heart failure in the United States alone. Statistics from the American Heart Association also suggest that new cases of heart failure are diagnosed at a rate of about 550,000 each year. Of the newly diagnosed patients fifty percent are likely to die within five years from the initial diagnosis. Of course, these numbers do not account for the number of patients in other countries who also suffer from heart failure. Given these numbers, it is clear that heart failure is a significant human crisis.[0003]Heart failure is a condition that is characterized, in part, by a reduced ability of the heart to circulate blood through the body. ...

Claims

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Application Information

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IPC IPC(8): C07K14/51C07K14/71C07K14/705C07K16/22A61P9/04
CPCC07K2319/30C07K16/22C07K14/51C07K2317/41A61P9/04A61K45/06C07K14/71C07K14/70596A61K38/00C07K2317/76A61P9/00A61K38/179A61K38/1875C12N9/12C07K14/4703C07K19/00
Inventor LI, GANGGRINBERG, ASYASAKO, DIANNE
Owner ACCELERON PHARMA INC
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